Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein

ABSTRACT

This invention relates to a novel process for the preparation of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors which contain a 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one moiety, such as compactin and mevinolin, by utilizing an alkyl 5(S),6-epoxy-3(R)-(alkoxy)hexanoate as a chiral synthon for the stereospecific introduction of the 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one moiety.

BACKGROUND OF THE INVENTION

Endo et al., J. Antibiotics, XXXIX, 1346 (1976) described a fermentationproduct, ML-236B, with potent antihypercholesterolemic activity whichacts by inhibiting HMG-CoA reductase. This material, named compactin byBrown et al., J. Chem. Soc., Perkin I, 1165 (1976) was shown to have adesmethyl mevalonolactone partial structure and the stereochemistry wasstudied.

Shortly thereafter a chemically similar, natural product MK-803(mevinolin), obtained by fermentation, was isolated and characterized,by Monaghan et al., U.S. Pat. No. 4,231,938. It has been shown to havethe same desmethyl mevalonolactone partial structure and the absolutestereochemical configuration has been determined and described in EPOpublication No. 0,022,478 of Merck & Co., Inc.

Totally synthetic analogs of these natural inhibitors have been preparedand described in Sankyo's U.S. Pat. No. 4,198,425 and Sankyo's U.S. Pat.No. 4,255,444 with no attempt being made to separate the stereo- andoptical isomers. Subsequently, as described in Merck's EPO publicationNo. 0,024,348 and by Meyer, Ann. Chem., (1979), pages 484-491, similartotally synthetic analogs were separated into their stereoisomers andoptical enantiomers. Furthermore, it was shown in EPO publication No.0,024,348 that essentially all of the HMG-CoA reductase activity residesin the 4(R)-trans species as is the case with the naturally occurringcompounds compactin and mevinolin.

In most of the prior art processes for preparing the totally syntheticcompounds, the lactone moiety of each compound has to be elaborated by alengthy series of synthetic operations followed by very tedious andexpensive chromatographic separation of the cis, trans racemates, orenantiomers, following which, the inactive cis-isomer would bediscarded.

A process for the preparation of the lactone ring system in the correctoptically active form was recently prepared by Majewski et al.,Tetrahedron Lett., 1984, 2101-2104 utilizing a (3S,5S) iodoketal of thefollowing formula: ##STR1##

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a novel process for the preparation ofantihypercholesterolemic agents of the following general structuralformula (I): ##STR2## wherein R¹ is selected from the group consistingof: ##STR3## wherein Q is ##STR4## R⁶ is H or OH; R is hydrogen ormethyl, and a, b, c, and d represent optional double bonds except when aand c are double bonds, R⁶ is not OH, especially wherein b and drepresent double bonds or a, b, c, and d are all single bonds; or##STR5## wherein R² and R³ are independently C₁₋₃ alkyl or halo (F, Clor Br) and R⁴ is hydrogen, phenyl, benzyloxy, substituted phenyl orsubstituted benzyloxy in which the phenyl group in each case issubstituted with one or more substituents selected from C₁₋₃ alkyl andhalo, which comprises:

(A) reacting a compound of the formula (II): ##STR6## wherein R⁵ is C₁₋₅alkyl or benzyl and R⁷ is C₁₋₅ alkyl, benzyl, C₂₋₅ alkoxyalkyl, such asCH₃ OCH₂, or C₃₋₆ alkoxyalkoxy lkyl, such as CH₃ OCH₂ CH₂ OCH₂, with acompound of the formula (III):

    R.sup.1 X                                                  (III)

wherein R¹ is defined above, X is a metal atom or metal complex selectedfrom Li, MgCl, MgBr, (CuMgCl)_(1/2) or (CuMgBr)_(1/2) or an alkali metal(Li, Na, or K) plus an aryl sulfonyl group selected from ##STR7##followed by the removal of the aryl sulfonyl group [Trost et al.Tetrahedron Lett., 1976, 3477] to afford a compound of the formula (IV):##STR8## (B) lactonizing the compound of the formula (IV) under standardacidic conditions to afford the compound of formula (V): ##STR9## and(C) removing the R⁷ group by suitable methods known in the art [T.Greene, Protective Groups In Organic Synthesis, John Wiley & Sons, 1981,pp 10-86] or with an organoboron halide to afford the compound offormula (I).

In a preferred embodiment, the compounds prepared by the process of thisinvention are those compounds of the formula (I) wherein R¹ is (a) andR⁶ is hydrogen and R is hydrogen or methyl and b and d represent doublebonds or a, b, c and d are single bonds.

In a second preferred embodiment, the compounds prepared by the processof this invention are those compounds of the formula (I) wherein R¹ is(b), R² and R³ independently are chloro, fluoro or methyl and R⁴ ishydrogen, 4-fluoro-3-methylphenyl or 4-fluorobenzyloxy. The mostpreferred compounds are those wherein (1) R² and R³ are methyl and R⁴ is4-fluoro-3-methylphenyl; (2) R² and R³ are methyl and R⁴ is4-fluorobenzyloxy; and (3) R² and R³ are chloro and R⁴ is hydrogen.

The reaction of the compound of the formula (II) with the compound ofthe formula (III) is conducted at a temperature between -78° and 0° C.,preferably at -78° C. with warming to -20° C. for a period of from 1 to12 hours, most preferably 1 hour at -78° C. and 1 hour at -23° C., in aninert solvent. Illustrative of such inert solvents are: ethers orthioethers or mixtures thereof, such as diethyl ether, tetrahydrofuran,dimethoxyethane, dimethylsulfide and the like.

The amounts of reactants that are employed in this reaction may varybetween 0.1 and 1.0 equivalents of the compound of the formula (II) toeach equivalent of the compound of the formula (III). However, 0.4equivalents of the compound of the formula (II) is preferred. Thecompound of the formula (III) wherein X is (CuMgBr)_(1/2) is a preferredreactant.

The lactonization of the compound of the formula (IV) is conducted at atemperature between 0° and 25° C., preferably at ambient temperature,for a period of from 1 to 12 hours, preferably 3 hours in an inertsolvent with a catalytic amount of an acid. Illustrative of such inertsolvents are: hydrocarbons, such as, hexane, toluene, benzene,cyclohexane and the like; and ethers, such as, diethylether,tetrahydrofuran, dimethoxyethane and the like. Illustrative of suchacids are organic acids, such as, p-toluenesulfonic, benzenesulfonic andthe like and inorganic acids, such as, hydrochloric. The preferred acidutilized in the lactonization is p-toluenesulfonic acid.

The removal of the R⁷ protecting group is conducted at a temperaturebetween -78° and 0° C., preferably at -78° C. for a period from 1 to 12hours, preferably 1 hour in an inert solvent in the presence of anorganoboron halide. Illustrative of such inert solvents are: chlorinatedhydrocarbons, such as, methylene chloride, chloroform, dichloroethane orlow melting mixtures thereof and the like.

The organoboron halide reactant is represented by the following formula:

    R.sup.8 R.sup.9 BY

wherein R⁸ and R⁹ independently are C₁₋₄ alkyl, phenyl or when takentogether with the boron atom to which they are attached from a 5, 6 or 7membered ring or a bicyclic ring and Y is chloro or bromo. The preferredorganoboron halide is dimethylboron bromide. The amount of theorganoboron halide utilized may vary between 1 and 10 equivalents foreach equivalent of the compound of the formula (V), with 4 equivalentsbeing preferred.

The starting materials are either known or readily prepared according tothe synthetic pathways described below.

For compounds of the formula (III) wherein R¹ is (a) and X is a metalatom or metal complex, Tetrahedron Lett., pp. 1373-6 (1983) describes aprocedure for preparing compounds which can be readily converted intothe desired compounds of the formula (III) using standard reactionconditions. For comounds of the formula (III) wherein X is ##STR10##Tetrahedron Lett., pp. 1655-8 (1984) describes a procedure for preparingcompounds which can be readily converted into the desired compounds ofthe formula (III) using standard conditions. The compounds of theformula (III) wherein R¹ is (b) are known in the art.

The compound of the formula (II) wherein R⁵ and R⁷ are described aboveare readily prepared according to the following synthetic pathway from(S)-malic acid: ##STR11##

(S)-Malic acid (1) is reduced under standard reduction conditions usingBH₃.THF and then ketalized with acetone to give compound (2). Compound(2) is subjected to a Swern oxidation to yield compound (3), which,without isolation, is treated under Wittig conditions with Ph₃ PCHCO₂ R⁵to give Compound (4). Compound (4) is hydrolyzed under acid conditionsand selectively protected to give Compound (5) wherein Pr is aprotecting group selected from benzoyl, acetyl, triphenylsilyl ortert-butyldiphenylsilyl, preferably t-butyldiphenylsilyl. Compound (5)is cyclized to Compounds (6) and (7) under basic conditions withconcomitant migration of the Pr group. Compound (7) may be isomerized tothe desired Compound (6) under basic conditions. Compound (6) isconverted to Compound (8) using an organoboron halide R⁸ R⁹ BY,preferably dimethylboron bromide. Compound (8) is treated with R⁷-halide to get Compound (9) which is treated with tetraalkylammoniumfluoride or an alkalimetal alkoxide to afford the compound of formula(II).

The following Examples illustrate the present invention and as such arenot to be considered as limiting the invention set forth in the claimsappended hereto.

EXAMPLE 1 Step (a): Preparation of(S)-1,2-O-Isopropylidenebutane-1,2,4-triol

To a cold (0° C.), well-stirred solution of (S)-malic acid (13.4 g, 100mmol) in 300 ml dry tetrahydrofuran, under argon, was added dropwise(via capillary) a tetrahydrofuran solution of borane-THF complex (300ml, 300 mmol) over a period of 3 hours. The cooling bath was removed andthe resultant slurry was stirred at room temperature for 15 hours. Thereaction mixture was then cooled to 0° C. and carefully treated with drymethanol (100 ml). After warming to room temperature, the solvent wasevaporated. The residue was evaporated three times with dry methanol(100 ml each) to ensure complete methanolysis of the reductionintermediate. Brief drying (0.1 mm) gave 10.3 g of the crude triol.

This material was dissolved in acetone (300 ml) and a catalytic amountof p-TsOH.H₂ O (0.95 g, 5 mmol) added. After 12 hours at roomtemperature the reaction mixture was quenched with triethylamine (0.70ml, 5 mmol) and concentrated. The resultant oil was dissolved in ether(400 ml) and washed with water (3×50 ml) and brine (50 ml) and driedover MgSO₄. Concentration and bulb-to-bulb distillation of the residue(air-bath temperature 85°-95° C., 0.15 mm; lit.¹ 55°-61° C., 0.05 mm)gave 11.7 g (80%) of the desired product. ¹ H NMR (CDCl₃) analysisshowed that this material contained <10% of the isomeric acetonide(S)-2,4-O-isopropylidene butane-1,2,4-triol¹,2 and was used withoutfurther purification. This material exhibited IR (film) 3450, 2950, 1380and 1050 cm⁻¹ ; ¹ H NMR (250 MHz, CDCl₃) δ 1.38 (s, 3H), 1.43 (s, 3H),1.79-1.88 (m, 2H), 2.55 (broad s, 1H), 3.61 (d, d, J=7.7 Hz, 1H), 3.80(t, J-5.9 Hz, 2H), 4.10 (d, d, J=7.0, 7.7 Hz, 1H), 4.28 (m, 1H).

Step (b): Preparation of Ethyl(E)-(S)-O-Isopropylidene-5,6-dihydroxy-2-hexenoate

A cold (-78° C.) stirred solution of oxalyl chloride (1.92 ml, 22 mmol)in 50 ml of dry methylene chloride, under argon, was treated with asolution of DMSO (3.55 ml, 50 mmol) in the same solvent (10 ml). Afterstirring at -78° C. for 10 minutes a solution of(S)-1,2-O-isopropylidene butane-1,2,4-triol (2.92 g, 20 mmol) in 15 mlof methylene chloride was added. The resultant slurry was stirred at-78° C. for 40 minutes, then treated with diisopropylethylamine (17.5ml, 100 mmol). The cooling bath was removed and the reaction mixture wasstirred at room temperature for 1 hour to afford a yellow solution of(S)-O-isopropylidene 4-oxy-butane-1,2-diol.

This solution was cooled to 0° C. and treated withcarbethoxymethylenetriphenylphosphorane (17.4 g, 50 mmol) at 0° C. for 1hour and at room temperature for 4 hours. The resultant solution wasdiluted with ether (300 ml), washed with water (3×50 ml), 10% aqueousNaHSO₄ (50 ml) and brine (2×50 ml) and dried over MgSO₄. Removal ofsolvent gave a viscous oil. Ether (150 ml) and hexane (150 ml) wereadded and the mixture kept at -10° C. for 15 hours. Filtration of thewhite precipitate (Ph₃ P═O) and removal of solvent gave the crudeproduct. Flash chromatography (hexane-ethyl actate 85:15) gave 3.60 g(84%) of ethyl (E)-(S)-O-isopropylidene-5,6-dihydroxy-2-hexenoate:[α]_(D) -18.0 (c 2.43, MeOH); IR (film) 2994, 1727, 1661, 1372, 1269,1172 and 1064 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.30 (t, J=7.0 Hz, 3H), 1.36 (s,3H), 1.43 (s, 3H), 2.39-2.60 (m, 2H), 3.59 (m, 1H), 4.07 (m, 1H),4.16-4.30 (buried m, 1H), 4.20 (q, J=7.0 Hz, 2H), 5.92 (d, t, J=15.5,1.5 Hz, 1H), 6.92 (d, t, J=15.5, 7.2 Hz); MS m/e (relative intensity)199 (43), 101 (100).

Anal. calcd. for C₁₁ H₁₈ O₄ : C, 61.66; H, 8.47. Found: C, 61.42; H,8.44.

Step (c): Preparation of Ethyl (E)-(S)-5,6-dihydroxy-2-hexenoate

To a solution ofethyl-(E)-(S)-O-isopropylidene-5,6-dihydroxy-2-hexenoate (5.35 g, 25mmol) in 100 ml tetrahydrofuran was added 1N HCl (66 ml). The reactionmixture was stirred at room temperature for 18 hours. NaCl (10 g) andethyl acetate (400 ml) were added. The organic layer was separated andwashed with brine (2×50 ml). The aqueous washings were extracted withethyl acetate (2×100 ml), the extracts washed with brine (25 ml) and theorganic layers combined. Drying (MgSO₄) and removal of solvent gave 4.04g (93%) of a viscous oil. This material exhibited: IR (film) 3400, 1720,1657 and 1040 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.28 (t, J=7.0 Hz, 3H), 2.25(broad s, 1H), 2.39 (m, 2H), 2.58 (broad s, 1H), 3.43-3.55 (m, 1H),3.63-3,73 (m, 1H), 3.81-3,92 (m, 1H), 4.18 (q, J=7.0 Hz, 2H), 5.91 (d,J=16 Hz, 1H), 6.96 (dt, J=16, 6.6 Hz, 1H).

Anal. calcd. for C₈ H₁₄ O₄ : C, 55.16; H, 8.10. Found: C, 55.52; H,8.08.

Step (d): Preparation of Ethyl(E)-(S)-6-t-butyldiphenylsiloxy-5-hydroxy-2-hexanoate

To a cold (0° C.), stirred solution of the diol from Step (c) (4.04 g,23.2 mmol) in 116 ml dry methylene chloride, under argon, wassequentially added diisopropylethylamine (6.08 ml, 34.8 mmol)4-dimethylamino pyridine (280 mg, 2.3 mmol) and t-butyldiphenylsilylchloride (7.54 ml, 29 mmol). The reaction mixture was stirred at 0° C.for 1 hour and then at room temperature for 18 hours. Water (100 ml) andether (400 ml) were added. The organic layer was separated, washed withwater (100 ml), saturated aqueous NaHCO₃ (50 ml), 10% aqueous NaHSO₄ (50ml), and brine (50 ml). Drying (MgSO₄) and removal of solvent gave thecrude product. Purification by flash chromatography (300 g, SiO₂,hexane-ethyl acetate 85:15) gave 9.41 g (98%) of essentially puremono-siloxy alcohol. This material exhibited: [α]_(D) -10.0 (c 1.23,MeOH); IR (film) 3480, 2940, 1723, 1658, 1594, 1431, 1114 and 704 cm⁻¹ ;¹ H NMR (CDCl₃) δ 1.07 (s, 9H), 1.28 (t, J=7.2 Hz, 3H), 2.36 (broad t,J=6.5 Hz, 2H), 2.53 (d, J=4.4 Hz, 1H), 3.53 (d, d, J=10.2, 6.7 Hz, 1H),3.67 (d, d, J= 10.2, 3.7 Hz, 1H), 3.85 (m, 1H), 4.18 (q, J=7.2 Hz, 2H),5.87 (d, J=15.5 Hz, 1H), 6.94 (d, d, J=15.5, 7.3 Hz, 1H), 7.34-7.49 (m,6H), 7.60-7.68 (m, 4H); MS m/e (relative intensity) 355 (5), 199 (100).

Anal. calcd. for C₂₄ H₃₄ O₄ Si: C, 69.87; H, 7.82. Found: C, 70.22; H,7.60.

Step (e): Preparation of Ethyl2(R)-(4(S)-tert-butyldiphenylsiloxytetrahydrofuran)acetate and its2(S),4(S)-isomer

To a cold (0° C.), stirred solution of ethyl(E)-(S)-6-tert-butyldiphenylsiloxy-(5)-hydroxy-2-hexenoate (9.41 g, 23.0mmol) in 200 ml dry ethanol, under argon, was added a solution of sodiumethoxide (2.3 mmol) in ethanol (30 ml). Stirring was continued at roomtemperature for 2 hours and at 65° C. for 4 hours. The reaction mixturewas then cooled to room temperature and quenched with acetic acid (2.3mmol). Concentration provided the crude product as a yellow oil (9.5 g).TLC (hexane-ethyl acetate, 4:1) and ¹ H NMR (250 MHz, CDCl₃) analyses ofthe crude product indicated the presence of the desired β (R_(f) 0.55)and α (R_(f) 0.53) product isomers in a ratio of 2:1 along with a smallamount of starting material. This material was purified in two batchesby careful flash chromatography (300 g SiO₂, eluant: hexane-ethylacetate, 95:5) to afford after concentration of the appropriatefractions 4.51 g of pure 2(R),4(S)-β-isomer.

Further elution of the column (hexane-ethyl acetate, 4:1) andcombination of the appropriate fractions gave 4.80 g of a mixture of the2(R),4(S)- and 2(S),4(S)-isomers along with a small amount of startingmaterial. This material was dissolved in ethanol (160 ml) andresubjected to the equilibration conditions (1.16 mmol NaOEt) at 65° C.for 5 hours. Work-up and purification as outlined above (300 g SiO₂,eluant: hexane-ethyl acetate, 95:5 then 4:1) gave 2.27 g of pure2(R),4(S)-β-isomer (total yield 6.77 g, 72%). [α]_(D) 7.81 (c 2.08,MeOH), IR (film) 3080, 2940, 1738, 1593, 1115 and 703 cm⁻¹ ; ¹ H NMR(250 MHz, CDCl₃) δ 1.06 (s, 9H), 1.26 (t, J=7.2 Hz, 1H), 1.55 (d, d, d,J=15.4, 9.6, 5.6 Hz, 1 H), 2.07 (d, d, d, J=15.4, 5.6, 1.8 Hz, 1H), 2.44(d, d, J=15.4, 5.9 Hz, 1H), 2.57 (d, d, J=15.2, 7.2 Hz, 1H), 3.72 (d, d,d, J=9.4, 2.6, 0.8 Hz, 1H), 3.84 (d, d, J=9.4, 4.6 Hz, 1H), 4.15 (q,J=7.2 Hz, 2H), 4.45 (m, 1H), 4.57 (m, 1H), 7.33-7.50 (m, 6H), 7.60-7.76(m, 4H); MS m/e (relative intensity) 355 (11), 199 (100).

Anal. calcd. for C₂₄ H₃₂ O₄ Si: C, 69.87; H, 7.82. Found C, 70.15; H,7.73.

Further elution of the column (hexane-ethyl acetate, 4:1) and collectionof the appropriate fractions gave 0.98 g (10%) of the2(S),4(S)-α-isomer. IR (film) 3081, 2942, 1738, 1593, 1113 and 705 cm⁻¹; ¹ H NMR (250 MHz, CDCl₃) δ 1.07 (s, 9H), 1.27 (t, J=7.2 Hz, 3H), 1.75(d, d, d, d, J=13.1, 5.7, 3.4, 0.9 Hz, 1H), 2.16 (d, d, d, J=13.1, 7.5,6.3 Hz, 1H), 2.66 (d, d, J=15.4, 6.4 Hz, 1H), 2.84 (d, d, J=15.4, 7.3Hz, 1H), 3.62 (d, d, J=9.4, 4.9 Hz, 1H), 3.81 (d, d, d, J=9.4, 2.8, 0.9Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 4.31 (m, 1H), 4.43 (m, 1 H), 7.33-7.50(m, 6H), 7.62-7.77 (m, 4H); MS m/e (relative intensity) 367 (14), 355(100), 199 (61).

Step (f): Preparation of Ethyl6-bromo-5(S)-tert-butyldiphenylsiloxy-3(R)-hydroxyhexanoate

To a cold (0° C.), stirred mixture of ethyl2(R)-(4(S)-tert-butyldiphenylsiloxytetrahydrofuran)acetate (1.21 g, 2.93mmol) and diisopropylethylamine (51 μl, 0.29 mmol) in 16.5 ml drymethylene chloride, under argon, was added a solution of dimethylboronbromide (3.46 ml, 5.98 mmol) in methylene chloride. The reaction mixturewas then stirred at room temperature for 2 hours, diluted with ether(100 ml) and quenched with saturated aqueous NaHCO₃ (10 ml). The organiclayer was separated, washed with 10 ml portions of saturated aqueousNaHCO₃, water and brine and dried over MgSO₄. Removal of solvent gave ayellow oil which was subjected to flash chromatography on silica gel(eluant: hexane-ethyl acetate, 4:1) to afford 1.19 g (82%) of thepurified product as a colorless oil. This material exhibited [α]_(D)+2.81 (c 1.67, MeOH); IR (film) 3430, 2938, 1725, 1590, 1430, 1112 and700 cm⁻¹ ; ¹ H NMR (250 MHz, CDCl₃) δ 1.08 (s, 9H), 1.26 (t, J=7.2 Hz,3H), 1.82 (m, 2H), 2.30 (m, 2H), 3.05 (broad s, 1H), 3.39 (d, J=3.7 Hz,2H), 4.10 (m, 1H), 4.15 (q, J=7.2 Hz, 2H), 7.34-7.48 (m, 6H), 7.64-7.70(m, 4H); MS m/e (relative intensity) 447 (4), 435 (2), 199 (100).

Anal. calcd. for C₂₄ H₃₃ O₄ SiBr: C, 58.41; H, 6.74. Found: C, 58.19; H,6.73.

Step (g): Preparation of Ethyl6-bromo-5(S)-tert-butyldiphenylsiloxy-(3)-(R)-(methoxymethoxy)hexanoate

To a cold (-10° C.), stirred solution of ethyl6-bromo-5(S)-tert-butyldiphenylsiloxy-(3)-(R)-hydroxyhexanoate (0.84 g,1.70 mmol) in 5.15 ml of dry acetonitrile, under argon, weresequentially added diisopropylethylamine (0.89 ml, 5.10 mmol),4-N,N-dimethylaminopyridine (21 mg, 0.17 mmol) and chloromethyl methylether (1.03 ml, 13.6 mmol). The argon inlet was removed and te reactionmixture was stored at -3° C. for 24 hours. The reaction mixture was thenquenched with saturated (aqueous) NaHCO₃ (3 ml) and diluted with ether(60 ml). The organic layer was separated, washed with saturated aqueousNaHCO₃ (2×10 ml), water (10 ml), 10% aqueous NaHSO₄ (10 ml) water (10ml) and brine (10 ml). Drying (MgSO₄) and concentration gave a paleyellow oil. Purification by flash chromatography on silica gel (60 g,eluant: hexane-ethyl acetate, 4:1) provided 0.85 g (94%) of pureproduct. This material exhibited: [α]_(D) =0.77 (c 1.68, CHCl₃); IR(film) 3075, 2935, 1738, 1589, 1428, 1031 and 701 cm⁻¹ ; ¹ H NMR (250MHz, CDCl₃) δ 1.08 (s, 9H), 1.24 (t, J=7.1 Hz, 3H), 1.94 (broad t, J=6.0Hz, 2H), 2.26 (d, d, J=15.3, 5.2 Hz, 1H), 2.39 (d, d, J=15.3, 7.3 Hz,1H), 3.18 (s, 3H), 3.37 (d, J=4.3 Hz, 2H), 3.92 (m, 1H), 4.04 (m, 1H),4.12 (q, J=7.1 Hz, 2H), 4.50 (d, J=7.1 Hz, A part of AB, 1H), 4.58 (d,J=7.1 Hz, B part of AB, 1H), 7.33- 7.46 (m, 6H), 7.65-7.74 (m, 4H); MSm/e (relative intensity) 479 (28), 213 (100).

Anal. calcd. for C₂₆ H₃₇ O₅ SiBr: C, 58.09; H, 6.97; Br, 14.86. Found:C, 58.33; H, 7.02; Br, 14.79.

Step (h): Preparation of Ethyl5(S),6-epoxy-3(R)-(methoxymethoxy)hexanoate

A cold (0° C.), stirred solution of ethyl6-bromo-5(S)-tert-butyldiphenylsiloxy-3(R)-(methoxymethoxy)hexanoate(0.80 g, 1.49 mmol) in 3.8 ml dry tetrahydrofuran (THF), under argon,was treated with a solution of tetra-n-butylammonium fluoride (4.47 ml,4.47 mmol; 1.0M solution in THF). The cooling bath was removed and thereaction mixture was stirred at room temperature for 3 hours. Ether (50ml) was then added and the mixture washed with water (5 ml), 10% aqueousNaHSO₄ (5 ml), water (5 ml) and brine (5 ml). Drying (MgSO₄) and removalof solvent gave a pale yellow oil which was subjected to flashchromatography on silica gel (20 g, hexane-ethyl acetate, 4:1) toprovide 0.241 g (74%) of the desired epoxide, [α]_(D) 31.5 (c 0.98,MeOH). IR (film) 2938, 1736 and 1035 cm⁻¹ ; ¹ H NMR (250 MHz, CDCl₃) δ1.23 (t, J=7.2 Hz, 3H), 1.70-1.82 (m, 1H), 1.86-1.99 (m, 1H), 2.49 (m,1H), 2.56 (d, d, J=15.6, 5.0 Hz, 1H), 2.71 (d, d, J=15.6, 6.0 Hz, 1H),2.77 (m, 1H), 3.08 (m, 1H), 3.38 (s, 3H), 4.16 (q, J=7.2 Hz, 2H), 4.29(m, 1H), 4.67 (d, A part of AB, J=7.8 Hz, 1H), 4.72 (d, B part of AB,J=7.8 Hz, 1H).

Anal. calcd. for C₁₀ H₁₈ O₅ : C, 55.03; H, 8.31. Found: C, 54.82; H,8.39.

EXAMPLE 2 Step (a): Preparation of 2,4-Dichlorobenzylmagnesium bromide

To stirred magnesium metal (0.121 g, 5 mmol) in 1.0 ml of dry ether,under argon, was added 0.5 ml of an ether solution of 2,4-dichlorobenzylbromide (1.20 g, 5 mmol in 4.0 ml dry ether). A small crystal of iodinewas added and initiation of the reaction took place (exothermic) within5 minutes. The remaining solution of 2,4-dichlorobenzyl bromide was thenadded dropwise at such a rate as to maintain a mild reflux. After theaddition was complete the reaction mixture was refluxed for 1 hour toafford a colorless solution of 2,4-dichlorobenzylmagnesium bromide inether (about 1.0M).

Step (b): Preparation of Ethyl7-(2,4-dichlorophenyl-5(R)-hydroxy-3(R)-(methoxymethoxy)heptanoate

To a cold (-78° C.), stirred suspension of cuprous bromide-dimethylsulfide complex (88 mg, 0.43 mmol) in a mixture of dimethyl sulfide (1.3ml) and ether (0.4 ml), under argon, was added dropwise a solution of2,4-dichlorobenzylmagnesium bromide (0.88 ml, 0.88 mmol; 1.0M in ether).The resultant orange solution was stirred at -78° C. for 15 minutes. Asolution of ethyl 5(S),6-epoxy-3(R)-(methoxymethoxy)hexanoate (72 mg,0.33 mmol) in 0.5 ml dry ether was then added dropwise over a period of3 minutes. The reaction mixture was stirred at -78° C. for 1 hour and at-23° C. for 1 hour. Saturated aqueous NH₄ Cl (0.5 ml) adjusted to pH 8with concentrated NH₄ OH, and ether (20 ml) were added. After warming toroom temperature the organic layer was separated, washed with 5 mlportions of saturated aqueous NH₄ Cl (pH 8), water and brine and driedover MgSO₄. Concentration and purification by flash chromatography onsilica gel (eluant: hexane-ethyl acetate, 7:3) gave pure product, 124 mg(100%). This material exhibited: [α ]_(D) +5.37 (c 0.85, MeOH); IR(film) 3480, 2943, 1738, 1591, 1477 and 1136 cm⁻¹ ; ¹ H NMR (250 MHz,CDCl₃) δ 1.26 (t, J=7.2 Hz, 3H), 1.66-1.87 (m, 4H), 2.50 (d, d, J=15.0,6.4 Hz, 1H), 2.71 (d, d, J=15.0, 6.3 Hz, 1H), 2.74-2.96 (m, 2H), 3.11(broad s, 1H), 3.39 (s, 3H), 3.80 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 4.22(m, 1H), 4.69 (d, A part of AB, J=6.7 Hz, 1H), 4.75 (d, B part of AB,J=6.7 Hz), 7.18 (m, 2H), 7.34 (m, 1H); MS m/e (relative intensity) 159(100).

Anal. calcd. for C₁₇ H₂₄ O₅ Cl₂ : C, 53.84; H, 6.38. Found: C, 53.91; H,6.50.

Step (c): Preparation of6(R)-[2-(2,4-dichlorophenyl)ethyl]-4(R)-(methoxymethoxy)tetrahydro-2H-pyran-2-one

A mixture of7-(2,4-dichlorophenyl)-5(R)-hydroxy-3(R)-(methoxymethoxy)heptanoate (100mg, 0.26 mmol) and p-TsOH.H₂ O (5 mg, 0.026 mmol) in 1.30 ml benzene,under argon, was stirred at room temperature for 3 hours. The reactionmixture was then diluted with ether (20 ml), washed with 2 ml portionsof saturated aqueous NaHCO₃, water and brine and dried over MgSO₄.Concentration and purification of the residue by flash chromatography(eluant: hexane-ethyl acetate, 4:1) afforded 78 mg (90%) of the desiredlactone, [α]_(D) +32.4 (c 0.71, MeOH). IR (film) 2940, 1740, 1590, 1475and 1040 cm⁻¹ ; ¹ H NMR (250 MHz, CDCl₃) δ 1.75 (m, 1H), 1.94 (m, 2H),2.07 (m, 1H), 2.65-3.05 (m, 4H), 3.35 (s, 3H), 4.20 (m, 1H), 4.63 (m,1H), 4.67 (s, 2H), 7.19 (s, 2H), 7.37 (s, 1H); MS m/e (relativeintensity) 332 (13), 159 (100).

Step (d): Preparation of6(R)-[2-(2,4-dichlorophenyl)ethyl]-4(R)-hydroxy-tetrahydro-2H-pyran-2-one

To a cold (-78° C.), stirred solution of the corresponding methoxymethylether derivative from Step (c) (65 mg, 0.20 mmol) in 1.50 ml drymethylene chloride, under argon, was added a solution of dimethylboronbromide (1.56M) (0.51 ml, 0.80 mmol) in methylene chloride. Stirring wascontinued at -78° C. for 1 hour. The reaction mixture was then added toa room temperature stirred mixture of tetrahydrofuran (2.0 ml) andsaturated aqueous NaHCO₃ (2 ml). After 3 minutes ether (20 ml) was addedand the organic layer washed with 2 ml portions of saturated aqueousNaHCO₃, water and brine. Drying (MgSO₄) and concentration gave the crudeproduct. Purification by flash chromatography (6 g, SiO₂, eluant:hexane-ethyl acetate, 4:1) gave 46 mg (79%) of the desired product,[α]_(D) +59.7 (c 1.10, CHCl₃). IR (film) 3440, 1728, 1476, 1260 and 1050cm⁻¹ ; ¹ H NMR (250 MHz, CDCl₃) δ 1.78 (m, 1H), 1.88-2.10 (m, 3H), 2.20(d, J=3.6 Hz, 1H), 2.64 (d, d, d, J=16, 3.4, 0.9 Hz, 1H), 2.76 (d, d,J=16, 4 Hz, 1H), 2.77-3.05 (m, 2H), 4.41 (broad m, 1H), 4.71 (broad m,1H), 7.18 (s, 2H), 7.36 (s, 1H); MS m/e (relative intensity) 288 (15),159 (100).

Anal. calcd. for C₁₃ H₁₄ O₃ Cl₂ : C, 54.00; H, 4.88. Found: C, 54.02; H,4.89.

EXAMPLES 3-12

Utilizing the general procedures of Example 2 and starting from theappropriately substituted compounds of the formula (III) and ethyl5(S),6-epoxy-3(R)-(methoxymethoxy)hexanoate the following compounds ofthe formula (I) are prepared:

    ______________________________________                                        Compound                                                                      Number     R.sup.1                                                            ______________________________________                                                    ##STR12##                                                         4                                                                                         ##STR13##                                                         5                                                                                         ##STR14##                                                         6                                                                                         ##STR15##                                                         7                                                                                         ##STR16##                                                         8                                                                                         ##STR17##                                                         9                                                                                         ##STR18##                                                         10                                                                                        ##STR19##                                                         11                                                                                        ##STR20##                                                         12                                                                                        ##STR21##                                                         ______________________________________                                    

What is claimed is:
 1. A process for the preparation of a compound ofthe following general structural formula (I): ##STR22## wherein R¹ isselected from the group consisting of: ##STR23## wherein Q is ##STR24##R⁶ is H or OH: R is hydrogen or methyl, and a and c, except when R⁶ isOH, or b and d represent double bonds or all of a, b, c, and d aresingle bonds; or ##STR25## wherein R² and R³ are independently C₁₋₃alkyl, fluoro, chloro or bromo; and R⁴ is hydrogen, phenyl, benzyloxy,substituted phenyl or substituted benzyloxy in which the phenyl group ineach case is substituted with one or more substituents selected fromC₁₋₃ alkyl, fluoro, bromo or chloro, which comprises:(A) reacting acompound of the formula (II): ##STR26## wherein R⁵ is C₁₋₅ alkyl orbenzyl; and R⁷ is C₁₋₅ alkyl, benzyl, C₂₋₅ alkoxyalkyl or C₃₋₆alkoxyalkoxyalkyl; with a compound of the formula (III):

    R.sup.1 X                                                  (III)

wherein R¹ is defined above and X is a metal atom or metal complexselected from Li, MgCl, MgBr, (CuMgCl)_(1/2) or (CuMgBr)_(1/2) to afforda compound of the formula (IV): ##STR27## (B) lactonizing the compoundof the formula (IV) at a temperature between 0° and 25° C. in an inertsolvent with a catalytic amount of an acid to afford the compound offormula (V): ##STR28## and (C) removing the R⁷ group with an organoboronhalide to afford the compounds of formula (I).
 2. A process of claim 1wherein R¹ is (a).
 3. A process of claim 2 wherein R⁶ is hydrogen and Ris hydrogen or methyl and b and d represent double bonds or each of a,b, c and d is a single bond.
 4. A process of claim 1 wherein R¹ is (b).5. A process of claim 4 wherein R² and R³ are independently chloro,fluoro or methyl and R⁴ is hydrogen, 4-fluoro-3-methylphenyl or4-fluorobenzyloxy.
 6. A process of claim 5 wherein R² and R³ are methyl.7. A process of claim 5 wherein R² and R³ are chloro and R⁴ is hydrogen.8. A process of the claim 1 wherein the organoboron halide isrepresented by the formula:

    R.sup.8 R.sup.9 BY

wherein R⁸ and R⁹ are independently C₁₋₄ alkyl, phenyl or when takentogether with the boron atom to which they are attached form a 5-, 6-,or 7-membered ring or a bicyclic ring and Y is chloro or bromo.
 9. Aprocess of claim 8 wherein the organoboron halide is dimethylboronbromide.